We propose to identify Slesl, an epistatic modifier that suppresses the development of fatal lupus in our B6- congenic model of systemic autoimmunity. In preliminary studies, we have localized this gene into a 956 Kb congenic interval on murine chromosome 17 and developed a strategy that allows the phenotypic detection of Slesl in mice at ~3 months of age. We now propose to identify this gene and characterize the molecular pathways and cell lineages that it modulates to suppress fatal lupus. We have two specific aims: Specific aim 1. To localize and identify Slesl. We will localize Slesl to a genomic segment of <200 Kb via phenotypic rescue using transgenic mice expressing a series of 86-derived BACs (bacterial artificial chromosomes) spanning the critical region. Suppression of autoimmunity by Slesl is recessive in crosses with B6, indicating that a 66-derived BAG containing the Slesl locus will cause B6.Sle1Sleslyaa mice to develop autoimmunity. A total of 7 B6-BAC transgenic strains will be required to span the Slesl critical interval, one of which will contain Slesl and cause autoimmune phenotypes in B6.Sle1Slesl mice. The genomic characteristics of the candidate genes within this BAGwill be analyzed in detail and Slesl will be definitively identified via in vivo analysis using BAC-modification technology to disrupt validated candidate genes located in the BAG. Specific aim 2. To define the molecular pathways and immunologic mechanisms by which Slesl suppresses disease. Our ongoing analysis of Slesl indicates that this gene modulates phenotypes expressed in B lymphocytes, T lymphocytes, and monocytes. The role of each lineage in the suppression of autoimmunity by Slesl will be determined by adoptive transfer and/or mixed bone marrow chimeras. In addition, we will utilize the Illumina Mouse-6 BeadChip for global gene expression analysis to identify genetic pathways that are modified by Slesl in each of these lineages. These analyses will characterize the immunologic mechanisms that mediate the suppression of autoimmunity by Slesl and provide important new insights into the immunologic processes that regulate immune tolerance and suppress incipient autoimmunity.